Monoamine Oxidase Inhibition Causes a Long-Term Prolongation of the Dopamine-Induced Responses in Rat Midbrain Dopaminergic Cells

The Journal of Neuroscience, April 1, 1997, 17(7):2267–2272

Nicola B. Mercuri, Mariangela Scarponi, Antonello Bonci, Antonio Siniscalchi, and Giorgio Bernardi Clinica Neurologica, Dipartimento Sanita´ Pubblica, Universita´ di Roma Tor Vergata and Istituto Ricerca e Cura a Carattere Scientiﬁco Ospedale Santa Lucia, Roma, Italy

The way monoamine oxidase (MAO) modulates the depression over, the effects of DA were not largely prolonged during the of the firing rate and the hyperpolarization of the membrane simultaneous inhibition of MAO and the DA reuptake system. caused by dopamine (DA) on rat midbrain dopaminergic cells Interestingly, the actions of amphetamine were not clearly aug- was investigated by means of intracellular recordings in vitro. mented by MAO inhibition. The cellular responses to DA, attributable to the activation of From the present data it is concluded that the termination of somatodendritic D2/3 autoreceptors, were prolonged and did DA action in the brain is controlled mainly by MAO enzymes. not completely wash out after pharmacological blockade of This long-term prolongation of the dopaminergic responses both types (A and B) of MAO. On the contrary, depression of the suggests a substitutive therapeutic approach that uses MAO firing rate and membrane hyperpolarization induced by quinpi- inhibitors and DA precursors in DA-deficient disorders in which role (a direct D2 receptor agonist) were not affected by MAO continuous stimulation of the dopaminergic receptors is inhibition. Furthermore, although the inhibition of DA reuptake preferable. by cocaine and nomifensine caused a short-term prolongation of DA responses, the combined inhibition of MAO A and B Key words: pargyline; cocaine; nomifensine; intracellular re- enzymes caused a long-term prolongation of DA effects. More- cordings; substantia nigra; ventral tegmental area

The time course of the action of dopamine (DA) on its receptors tive mechanism of termination of DA action in the brain occurs has been believed to be controlled primarily by the DA reuptake via its deamination by MAO. system. This assumption has been substantiated by extensive studies demonstrating that the concentration of DA (Church et al., MATERIALS AND METHODS 1987; Di Chiara and Imperato, 1988; Galloway, 1988; Nomikos et Preparation of the tissue. The method used has been described previously al., 1990; Kalivas and Duffy, 1991) and the physiological effects of (Mercuri et al., 1995). In brief, Wistar rats (150–250 gm) were anesthe- tized with ether and killed. The brain was removed, and horizontal slices this catecholamine in the brain are enhanced by agents that are (thickness 300 ␮m) were cut by a vibratome starting from the ventral able to block its transporter (Einhorn et al., 1988; Williams and surface of the midbrain. In some experiments in which amphetamine was Lacey, 1989; Lacey et al., 1990; Mercuri et al., 1991a,b,c). It has used, coronal slices of the ventral mesencephalon were also cut (Lacey et been suggested, however, that the tone of DA is regulated not al., 1987). A single slice containing the substantia nigra and the ventral tegmental area (VTA) was then transferred into a recording chamber and only by the DA reuptake system but also by the DA synthesizing submerged completely in an artificial cerebrospinal fluid with a continu- and degrading enzymes. Accordingly, we have shown recently that ously flowing (2.5 ml/min) solution at 35ЊC, pH 7.4. This solution con- stimulation of DA synthesis by levodopa (Mercuri et al., 1990) tained (in mM): 126 NaCl, 2.5 KCl, 1.2 MgCl2, 1.2 NaH2PO4, 2.4 CaCl2, and blockade of DA degradation by MAO inhibitors (MAOI) 11 glucose, 20 NaHCO3, gassed with 95% O2/5% CO2. (Mercuri et al., 1996) cause a DA-mediated depression of the Recordings. The recording electrodes (Clark 1.0–1.5 mm, thick wall), pulled by Narishige vertical and horizontal pullers, were filled with 2 M firing discharge of the dopaminergic neurons in the ventral KCl and had a tip resistance of 40–80 M⍀. The signals were obtained by mesencephalon. an amplifier (Axoclamp-2A, Axon Instruments, Foster City, CA) and To study possible changes in the DA-induced responses caused displayed on a pen recorder (Gould 2400 S) and on a digital oscilloscope by the inhibition of MAO enzymes, we made intracellular elec- (Tektronix) or saved on a tape recorder (Biologic) for off-line analysis. The tips of the electrodes were placed in the substantia nigra pars trophysiological recordings from dopaminergic neurons in the rat compacta (SNc) and VTA by using a dissecting microscope. mesencephalon maintained in vitro. Using the same preparation, Application of drugs. Drugs were made in stock solutions and bath- we also examined the effects of two DA reuptake inhibitors, applied at known concentrations via a three-way tap system. A complete cocaine and nomifensine, on responses to exogenously applied exchange of the solution in the recording chamber occurred in ϳ1 min. DA. Contrary to the common belief that the effects of DA are The following substances were used: DA hydrochloride; cocaine hydrochloride; (ϩ)-amphetamine sulfate; haloperidol; pargyline, which regulated mainly by the transporter, we found that a more effec- blocks both types of MOA (A and B) (Butcher et al., 1990), (Sigma, St. Louis, MO); quinpirole (LY 171555, Lilly); nomifensine (Hoechst- Received Dec. 6, 1996; revised Jan. 6, 1997; accepted Jan. 13, 1997. Roussel Pharmaceuticals, Frankfurt, Germany); clorgyline, which is more We thank G. Gattoni, M. Federici, and M. Tolu for their excellent technical selective for type A MAO (Johnston, 1968); and deprenyl, which is more assistance. selective for type B MAO (Knoll and Magyar, 1972) (Research Biomedi- Correspondence should be addressed to Dr. Nicola B. Mercuri, IRCCS, Santa cals, Natick, MA); and L-sulpiride (Ravizza). The changes in firing rate Lucia, Via Ardeatina, n. 306, 00179, Roma, Italy. induced by the drugs were normalized as a percentage of control (each Copyright ᭧ 1997 Society for Neuroscience 0270-6474/97/172267-06$05.00/0 neuron served as its own control). In some experiments the slices were 2268 J. Neurosci., April 1, 1997, 17(7):2267–2272 Mercuri et al. • Long-Term Prolongation of DA Responses

Figure 1. Pargyline prolongation of DA responses. A, The bath application of DA (30 ␮M) produced a reversible hyperpolarization and inhibition of firing. The bar indicates the period of DA application. A long-term prolongation of the DA-induced hyperpolarization and inhibition (DA was applied for the same period of control) was observed when pargyline 10 ␮M was superfused on the cells for 30 min. The subsequent application of sulpiride (300 nM) antagonized the prolonged response to DA application. B, The inhibitory effects of quinpirole (100 nM) were not affected by the superfusion of pargyline (10 ␮M) for 30 min. Note that in this and the following figures the speed of the chart was changed at the points indicated (see x underneath) to show individual action potentials. Full amplitude of the action potential was not reproduced because of the limited frequency of the pen recorder. preincubated for 2–3 hr with pargyline (1–10 ␮M), clorgyline (1–30 ␮M), or deprenyl (1–10 ␮M) to allow sufficient time for steady-state MAO inhibition to develop (Harsing and Vizi, 1984), and then the neuronal responses to DA were evaluated. Data were expressed as mean Ϯ SEM. RESULTS Electrophysiological and pharmacological properties of DA cells The present results are based on intracellular recordings made from 120 spontaneous-firing midbrain dopaminergic cells in vitro. The properties of these “principal” neurons have been described (Llinas et al., 1984; Kita et al., 1986; Grace and Onn, 1989; Lacey et al., 1989; Johnson and North, 1992; Mercuri et al., 1995). They fired at a mean rate of 1.5 Hz, had a relatively long-lasting spike (Ͼ1.2 msec), and showed a voltage-dependent sag in membrane potential with hyperpolarizing pulses. A brief superfusion of DA (10–30 ␮M for 1–2 min) caused reversible membrane hyperpolarization and inhibition of spontaneous firing. When application of the solution containing DA was discontinued, the firing rate returned to basal value within 5–10 min (Figs. 1A, 2). A reversible inhibition of the spontaneous firing and a hyperpolarization were also observed when quinpirole (30 nM–1 ⌴M for 30–60 sec) (n ϭ 7) or (ϩ)amphetamine (10–20 ␮M) were bath-applied to these neurons (n ϭ 6) (Figs. 1B, 6). The cellular responses to DA and quinpirole application are attributable mainly to the activation of somatodendritic D2/D3 type receptors, which increases potassium conductance (Lacey et al., 1987). Furthermore, the membrane hyperpolarization and the depression of the spontaneous discharge caused by amphetamine are attributable to the release of endogenous DA from calcium-insensitive stores (Mercuri Figure 2. Long-term prolongation of the DA-responses in pargyline and et al., 1989). effects of the combined perfusion of DA uptake blockers. a, Plot of the firing rate (percentage of control) versus time in control condition and The inhibition of MAO potentiates the effects of after a treatment with pargyline (10 ␮M). Note that pargyline produced an exogenously applied DA but not the effects enduring DA-induced firing inhibition. The bar illustrates the DA washout of quinpirole starting point. Note that the firing remained depressed even after 160 min After testing the effects of DA and quinpirole on the principal of DA washout. In b, the previous graph was superimposed with two other graphs to observe the different changes in DA responses caused by cells, these cells were then superfused with the nonspecific MAO pargyline alone or in combination with cocaine (3 ␮M) and nomifensine A and B inhibitor pargyline (1–100 ␮M for 20–50 min). At a (10 ␮M). Data were obtained from 4–10 determinations. Error bars concentration of 100 ␮M, pargyline often reduced the spontaneous represent SEM. Mercuri et al. • Long-Term Prolongation of DA Responses J. Neurosci., April 1, 1997, 17(7):2267–2272 2269

Figure 4. Effects of deprenyl on DA-induced responses. A, The superfusion of DA induced a reversible inhibition of this principal cell. B, After the bath application of deprenyl the depressant effect of DA was poten- Figure 3. Effects of clorgyline on the DA-induced responses. A, Control tiated. This long-lasting inhibition was antagonized by sulpiride (100 nM). response to DA application. B, Long-term prolongation of DA-induced inhibition after clorgyline treatment. Note that sulpiride was able to restore the control firing discharge of the cells, indicating a protracted in DA-induced responses was also observed in neurons pretreated activation of the somatodendritic D2-like autoreceptors. with either clorgyline (30 ␮M) or deprenyl (10 ␮M) (three cells for each compound), whereas lower concentrations (1–3 ␮M) were discharge of the neurons (Mercuri et al., 1996). We tried to not effective (not illustrated). counteract this inhibitory effect, however, by injecting steady-state Comparison of DA effects during MAOI with DA depolarizing current into the cells before testing DA again. In all actions during reuptake inhibition neurons (n ϭ 40) treated with pargyline (3–100 ␮M) the inhibition In the presence of cocaine (3 ␮M) and nomifensine (10 ␮M), the and hyperpolarization caused by DA were prolonged, and in most amplitude and duration of cellular responses (inhibition of firing cases these effects did not recover completely even after 1 hr or and membrane hyperpolarization) to DA (10 ␮M, 1 min) appli- more of washout (Figs. 1A, 2). Conversely, the cellular effects cation were increased (Fig. 5). Both cocaine and nomifensine caused by the direct D2 agonist quinpirole were not affected by decreased the firing activity of the dopaminergic cells (from 15 to MAO inhibition (Fig. 1B)(nϭ5). 40% of control) by hyperpolarizing the membrane (1–4 mV) Although we observed a slight prolongation of the DA-induced (Lacey et al., 1990; Mercuri et al., 1991a,b,c); however, to rees- responses with 1 ␮M pargyline (three of five cells), the threshold tablish the control firing rate, depolarizing current (10–40 pA) for significant action of this drug was 3 ␮M. Once a sustained DA was injected into the cells before DA was applied again. inhibition was induced in pargyline-treated neurons, it could be Figure 5, Ab and Bb, shows two graphs in which we plotted the readily reversed by superfusion of the D2/D3 receptor antagonist firing rate percentage at different intervals after DA application in sulpiride (100 nM–1 ␮M) (Fig. 1A)(nϭ10) and haloperidol (10 control conditions and in cells treated with cocaine (3 ␮M for 4–9 ␮M)(nϭ4) (not shown). In some cells treated with pargyline, min) or nomifensine (10 ␮M for 4–9 min). It is clear that although however, not even the application of sulpiride (n ϭ 8) or halo- a long-term prolongation of the inhibitory effect of DA was peridol (n ϭ 2) fully antagonized the long-lasting depressant caused by pargyline, only a short-term prolongation of the DA- effects caused by DA. induced firing depression was caused by cocaine or nomifensine. An enduring change in the DA-induced inhibition was also obtained in cells pretreated with pargyline (3–10 ␮M)(nϭ15) The simultaneous inhibition of MAO and the DA (not illustrated). reuptake system prevents the MAOI-induced A long-lasting prolongation of the DA-induced inhibition was enhancement of DA responses obtained by superfusion of either the preferential MAO A or B When pargyline (10 ␮M for 20–40 min) and nomifensine (3 ␮M) inhibitors clorgyline and deprenyl, respectively, at concentrations (n ϭ 5) or cocaine (3 ␮M)(nϭ6) were perfused simultaneously ranging from 10 to 30 ␮M for 30–40 min (four cells for each on the dopaminergic cells, no long-term prolongation of DA compound) (Figs. 3, 4). At lower concentrations (300 nM–3 ␮M) responses was observed, but only a reversible potentiation of DA these substances were ineffective. A similar, long-lasting increase effects was seen (Figs. 2, 5). 2270 J. Neurosci., April 1, 1997, 17(7):2267–2272 Mercuri et al. • Long-Term Prolongation of DA Responses

Figure 5. Effects of DA uptake inhibitors on DA-induced responses. Aa, Potentiation of the DA responses by cocaine (3 ␮M) and prevention of the pargyline-induced long-term prolongation of DA inhibition. Ab, The graph shows the cocaine-induced short-term prolongation of the inhibitory period caused by DA (each point represents four to six determinations). Ac, Prevention of the long-term prolongation of the DA-induced inhibition in the presence of cocaine (3 ␮M). Ba, Potentiation of DA responses by nomifensine. In the presence of pargyline plus nomifensine the long-term prolongation of the DA-induced inhibitory effect caused by pargyline was not observed. Bb, The graph shows the nomifensine-induced short-term prolongation of the DA-induced inhibitory period (each point represents four to ﬁve determinations). Bc, Prevention of the long-term prolongation of the DA-induced inhibition in the presence of nomifensine (10 ␮M). Note that the graphs in Ac and Bc are shown superimposed in Figure 2b. Mercuri et al. • Long-Term Prolongation of DA Responses J. Neurosci., April 1, 1997, 17(7):2267–2272 2271

leads to continued stimulation of the DA autoreceptors, which in some cells become resistant to washout or antagonism (Lacey et al., 1987; Bowery et al., 1994). This phenomenon could explain why the D2 antagonists sulpiride and haloperidol were not able to completely reverse the DA-induced depression of firing in some experiments. A further confirmation that the long-term prolongation of DA responses is attributable to its impaired degradation is provided by the fact that the electrophysiological effects of quinpirole (a direct D2 receptor agonist that is not a substrate for MAO enzymes) were not changed during MAO inhibition. More- over, the observation that the cellular responses to quinpirole were not prolonged after MAO inhibition seems to rule out the possibility that the long-term prolongation of DA actions is attributable to MAOI-induced changes in receptor sensitivity. Although the presence of MAO in the dopaminergic cells is still controversial, the existence of MAO A and B enzymes in the ventral mesencephalon has already been shown in the rat and human brain (Roffler-Tarlov et al., 1971; Marsden et al., 1972; Levitt et al., 1982; Commissioning, 1985; Saura et al., 1992, 1996), and their inhibition Figure 6. Effects of pargyline on amphetamine-induced responses. A, regulates DA metabolism (Houslay et al., 1976; Green et al., 1977; Control response to amphetamine. B, After pargyline application (30 min), the membrane hyperpolarization and the inhibition of firing caused Schoepp and Azzaro, 1982; Harsing and Vizi, 1984; Kito et al., 1986; by amphetamine were slightly potentiated. Butcher et al., 1990; Juorio et al., 1994). The blockade of both forms of MAO is a necessary The inhibition of MAO induces a short-term requisite for DA prolongation prolongation of the effects of endogenous DA It is interesting to note that only a pharmacological treatment that To test whether the blockade of MAO would enhance the effects inhibits both isoforms of MAOs was able to cause a prolongation of exogenously applied DA as well as the electrophysiological of DA effects on the dopaminergic neurons of the rat midbrain. In effects caused by endogenous (amphetamine-released) DA, we fact, the prolongation of DA responses was obtained with micro- designed experiments in which amphetamine was tested before molar concentrations of pargyline, clorgyline, and deprenyl. These and after the bath application of pargyline (10–30 ␮M). Under levels of the three drugs were thought to be nonselective, because these conditions, the reversible membrane hyperpolarization and they could irreversibly affect either MAO A or B enzymes inhibition of firing caused by the superfusion of (ϩ)amphetamine (Harsing and Vizi, 1984). This is in agreement with biochemical (10–20 ␮M) were slightly potentiated (13.1 Ϯ 2.8% of control; n ϭ findings showing that DA is a substrate for both forms of MAOs 9) (Fig. 6) after pargyline treatment (30 min). To rule out the (Houslay et al., 1976; Green et al., 1977; Flower et al., 1982; possibility that the lack of effect of pargyline on amphetamine Schoepp and Azzaro, 1982, 1983; Harsing and Vizi, 1984; Butcher responses was caused by impaired diffusion of the drug in the et al., 1990; Juorio et al., 1994) and with our recent electrophys- damaged/cut border of the horizontal slices, three experiments iological data showing that a depression of the spontaneous firing were conducted to check the effects of amphetamine under MAO discharge of the dopaminergic cells is caused by the simultaneous inhibition on dopaminergic cells of the SNc that were impaled in inhibition of MAO A and B enzymes (Mercuri et al., 1996). coronal slices. Even under these conditions, however, pargyline did not clearly enhance the effects of amphetamine. Interpretation of the effects of amphetamine and DA reuptake inhibitors DISCUSSION An increased content of intracellular and then extracellular DA after The main finding of the present study is that the termination of MAO inhibition might be the necessary requisite for the long-lasting DA action in the CNS is controlled more effectively by MAO inhibitory effect of exogenously applied DA. When the intracellular enzymes than by the DA reuptake system. In fact, the ability of DA stores are saturated, they cannot buffer any further increase in MAO inhibitors to induce an enduring prolongation of the elec- DA concentration caused by the bath application of this catechol- trophysiological effects of exogenously applied DA is most likely amine. Thus, as a consequence of intracellular DA saturation, the attributable to the blockade of MAO activity. Thus, although the extracellular levels of DA remain elevated. During amphetamine- rapid reuptake processes might contribute toward regulating the induced DA release, however, the DA stores are depleted again in cleavage of DA from their receptors for a relatively short period spite of MAO inhibition. Under these conditions, the neuronal of time, the degrading processes might play a major role in responses to amphetamine may recover partially, because extracel- maintaining a dopaminergic signal in the brain for a longer period lular DA is effectively removed by the reuptake system and subse- of time. This long-lasting increase in DA transmission is very quently redistributed in the neurons to restore the depleted pools. likely a consequence of the drug-induced blockade of DA deami- This phenomenon may explain why the amphetamine-induced re- nation by MAO at the mitochondrial membranes (Yang and Neff, sponses were not prolonged greatly by MAOI. Because we did not 1974; Green et al., 1977; Weiner and Molinoff, 1989; Juorio et al., observe a clear-cut prolongation of the responses caused by the 1994), so that there is a buildup of the intracellular and conse- amphetamine-induced release of DA from dendritic trees located in quently the extracellular concentration of this catecholamine. the horizontal and coronal planes of the mesencephalon, it is unlikely Under MAO inhibition, the DA reuptake system is probably fully that the scanty potentiation of amphetamine actions by MAOI are operating. Thus, it might fail to limit the physiological effects of dependent on a distinct distribution of MAO enzymes in the different newly applied DA. The impaired cleavage of extracellular DA planes of the mesencephalic slices. 2272 J. Neurosci., April 1, 1997, 17(7):2267–2272 Mercuri et al. • Long-Term Prolongation of DA Responses

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